This invention relates to new chemical entities of the General Formula 1 as shown below, composition containing said chemical entities and to methods of using said chemical entities for the prevention and treatment of pain. 
wherein n is equal to 1,2 or 3, A represents an aromatic substituent such as phenyl or a substituted phenyl, Z represents two hydrogen atoms or an oxygen atom, the (CH2)n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula 
in which R1 and R2 may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, D represents a group of the formula 
in which R3 represents hydrogen, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, R4 represents a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms or a lower alkenyl or alkynyl radical containing 2 or 3 carbon atoms, whereby R1 and R2 may be identical or different and may also form together with the adjacent nitrogen atom a nitrogeous heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino and piperazino rings. D may also represent a piperidine group, where the nitrogen substituent is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl or hydroxybutyl and where the piperidine nucleus is attached at 2-, 3- or 4-position.
The chemical compounds of this invention have pharmacological properties that render said compounds to be useful in preventing and treating pain. The compounds can also be used to treat conditions, comprising convulsions, hiccup and cardiac arrhythmias and can be used to inhibit sodium and potassium ion fluxes over cell membranes in the body.
Prevention and treatment of pain using the compounds of this invention may be achieved by applying compositions containing said chemical entities on the skin or by applying compositions containing said chemical entities on mucosal membranes or by injecting solutions of said chemical entities to infiltrate biological tissues with said solutions or by injecting solutions of said chemical entities in the anatomical vicinity of nerves, thereby allowing said chemical entities to penetrate the biological tissues and cause dermal anesthesia, topical anesthesia, infiltration anesthesia or nerve blocks.
The invention also refers to compositions, containing at least one of said chemical entities and combinations of the present chemical entities with various other chemical entities and with various penetration promoting devices.
Membrane stabilizing agents, such as lidocaine, prilocaine, mepivacaine and bupivacaine, have been shown to possess local anesthetic effects and are widely used for infiltration anesthesia and for inducing nerve blocks. These compounds have limited use as dermal anesthetics since they have to be given in high concentrations, which increases the risk of tissue irritation and tissue damage. Other compounds, such as tetracaine, are better suited for dermal anesthesia since they may better penetrate through the tissues. However, tetracaine and similar drugs are esters and are known to cause tissue irritation and to be unstable in the human body where practically all tissues contain esterases.
Objectives of the present invention are to obtain compounds that are potent membrane stabilizing agents with a prolonged effect as local anesthetics and topical anesthetics and dermal anesthetics and that have beneficial penetration properties and are able to penetrate the ocular tissues as well as mucosal tissues, including rectal tissues, and also penetrate through human skin after topical dermal application. Thus, the compounds of the invention will assure short onset time and long duration of local anesthesia, topical anesthesia and dermal anesthesia.
It is also an objective of the present invention to provide a method for local, topical and dermal anesthesia which is safe, effective, and has a minimum of side effects.
The mechanism of action of membrane stabilizing agents, when used as local anesthetic or topical anesthetic drugs, is to inactivate ion channels in nerves and thereby inhibit neuronal impulse conduction. To do this, the membrane stabilizing compound needs to overcome the local penetration barriers and reach the nerve structure in a concentration that is high enough to achieve the therapeutic objective. The compounds of the present invention have the ability to effectively overcome such tissue penetration barriers.
The term topical anesthesia is in this document defined as local anesthesia of mucosal membranes, such as for examples those of the eye, the ear, the mouth, the nose, the rectal area and the urogenital tract. The term dermal anesthesia is in this document defined as local anesthesia of the skin. Infiltration anesthesia and nerve blocks of afferent or efferent nerves are in this document called local anesthesia.
The present invention relates to new nerve membrane stabilizing compounds as described above and to methods of inducing local, topical or dermal anesthesia, by administering a composition containing at least one such chemical entity that has such penetration properties that it in a short period of time can reach the site of action on the nerve ending or a nerve in a concentration that will block the initiation or conduction of nerve impulses. It has been found that compositions containing at least one of the compounds of the present invention are particularly useful for ocular and dermal anesthesia and for other forms of local anesthesia, such as for example infiltration anesthesia and nerve blocks. The compounds of the present invention are useful for the prevention of pain in connection with inserts of injection needle, surgical procedures and for the treatment of pain in connection with the above mentioned medical procedures, insect bites, sunburn, and for the treatment of shingles and urogenital pain, including hemorrhoids.
Thus, the present invention provides effective methods for treating humans and animals with topical, dermal and local anesthetic compositions, while reducing undesirable side effects, for example local burning and itching and particularly tissue toxicity resulting in necrosis.